Process for preparing azabicyclic compounds

ABSTRACT

The present invention relates to a process for preparing azabicyclic compounds that are useful intermediates for synthesizing pharmaceutical compounds or salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 61/243,477 filed on Sep. 17, 2009. The entire contents of theaforementioned application are incorporated herein.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for preparing azabicycliccompounds that are useful in the synthesis of pharmaceutical compoundsand salts thereof.

BACKGROUND OF THE INVENTION

7-azabicyclo[2.2.1]heptanes are useful intermediates in the synthesis ofpharmaceutical compounds and salts thereof. For example, see U.S. Pat.Nos. 6,117,889 and 6,060,473, each of which is hereby incorporated byreference in its entirety.

SUMMARY OF THE INVENTION

What is disclosed herein is a process for preparing azabicycliccompounds that are useful intermediates for preparing pharmaceuticalcompounds and salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Compounds and processes disclosed herein include those describedgenerally above, and are further illustrated by the classes, subclasses,and species disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated.

The term “modulating” as used herein means increasing or decreasing by ameasurable amount.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent.

Unless otherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group, and when morethan one position in any given structure may be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at every position. Combinations ofsubstituents envisioned by this invention are preferably those thatresult in the formation of stable or chemically feasible compounds. Theterm “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.Such compounds, particularly compounds that contain deuterium atoms, mayexhibit modified metabolic properties.

In one aspect, the invention includes a process for preparing Compound7,

-   -   or a pharmaceutically acceptable salt thereof, comprising        contacting trans-4-aminocyclohexanol with Boc anhydride to        produce a compound of formula A

-   -   contacting a compound of formula A with methanesulfonic acid to        produce a compound of formula B

-   -   contacting a compound of formula B with trifluoroacetic acid to        produce a compound of formula C

-   -   contacting a compound of formula C with hydroxide to produce a        compound of formula 7.

In some embodiments, the invention includes a method of producing acompound of formula 7a,

-   -   comprising contacting a compound of formula 8 with hydrochloric        acid.

In one embodiment, trans-4-aminocyclohexanol is contacted with Bocanhydride in the presence of a solvent and optionally in the presence ofa base.

In another embodiment, the solvent comprises water, dichloromethane,THF, 2-methyltetrahydrofuran, ethanol, methanol, isopropanol, DMF, DMSO,or combinations thereof.

In one embodiment, the solvent is a mixture.

In a further embodiment, the solvent is a mixture comprising water anddichloromethane.

In one embodiment, a base is present and the base comprises sodiumbicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate, or combinations thereof.

In another embodiment, a compound of formula A is contacted withmethanesulfonic acid in the presence of a solvent and optionally in thepresence of a base.

In one embodiment, the solvent comprises tetrahydrofuran.

In another embodiment, a base is present and the base comprises atertiary amine base.

In a further embodiment, the base is triethylamine.

In one embodiment, the compound of formula B is contacted withtrifluoroacetic acid in the presence of a solvent.

In a further embodiment, the solvent is dichloromethane.

In another embodiment, the compound of formula B is contacted withtrifluoroacetic acid under neat conditions.

In one embodiment, the compound of formula C is contacted with hydroxidein the presence of a solvent.

In a further embodiment, the hydroxide is present as sodium hydroxide orpotassium hydroxide and the solvent comprises water.

In one embodiment, the process further comprises distillation of thereaction mixture and recovery of a compound of formula 7 in a pure form.

In one embodiment, the process further comprises recrystallizingCompound 7a from acetonitrile.

In another embodiment, the process further comprises recrystallizingCompound 7a from a mixture of methanol and 2-methyltetrahydrofuran.

In one embodiment, the ratio of methanol to 2-methyltetrahydrofuran isabout 1:1.

Formulations

The pharmaceutically acceptable compositions that can include theazabicyclic compound of the present invention or pharmaceuticalssynthesized therefrom may additionally comprise a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, which, as used herein,includes any and all solvents, diluents, or other liquid vehicle,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compounds of the invention may be formulated in dosage unit form forease of administration and uniformity of dosage. The expression “dosageunit form” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific effective dose levelfor any particular patient or organism will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “patient”, as used herein, means an animal, preferably a mammal,and most preferably a human.

The pharmaceutically acceptable compositions can be administered tohumans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, drops or patch), bucally, as an oral or nasal spray,or the like, depending on the severity of the infection being treated.In certain embodiments, the compounds of the invention may beadministered orally or parenterally at dosage levels of about 0.01 mg/kgto about 50 mg/kg and preferably from about 0.5 mg/kg to about 25 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound, it is often desirable toslow the absorption of the compound from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the compound then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administeredcompound form is accomplished by dissolving or suspending the compoundin an oil vehicle. Injectable depot forms are made by formingmicroencapsule matrices of the compound in biodegradable polymers suchas polylactide-polyglycolide. Depending upon the ratio of compound topolymer and the nature of the particular polymer employed, the rate ofcompound release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping the compound inliposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions can be employed in combination therapies, thatis, the compounds and pharmaceutically acceptable compositions can beadministered concurrently with, prior to, or subsequent to, one or moreother desired therapeutics or medical procedures. The particularcombination of therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that the therapies employed mayachieve a desired effect for the same disorder (for example, aninventive compound may be administered concurrently with another agentused to treat the same disorder), or they may achieve different effects(e.g., control of any adverse effects). As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated.”

The amount of additional therapeutic agent present in the compositionswill be no more than the amount that would normally be administered in acomposition comprising that therapeutic agent as the only active agent.Preferably the amount of additional therapeutic agent in the presentlydisclosed compositions will range from about 50% to 100% of the amountnormally present in a composition comprising that agent as the onlytherapeutically active agent.

Preparation of Azabicyclic Compounds

Preparation of trans-4-(tert-butoxycarbonylamino)cyclohexanol (A),method 1. Sodium carbonate (920.2 g, 8.682 mol, 2 eq) was added to areaction vessel followed by an addition of water (3.000 L, 6 vol) andstirring. Dichloromethane (DCM, 4.000 L, 4 vol) was added followed bytrans-4-aminocyclohexanol (500.0 g, 4.341 mol) to generate a biphasicreaction mixture that was vigorously stirred at room temperature. Asolution of Boc₂O (947.4 g, 997.3 mL, 4.341 mol, 1 eq) in DCM (2 vol)was then rapidly added dropwise to the vessel, and the resultingreaction mixture was stirred at room temperature overnight. The reactionmixture was then filtered and the filter cake was washed with water (2×8vol). The product was suction-dried until it was a compact cake. Thecake was then dried in a vacuum oven at 35° C. for 24 h giving 830 g oftrans-4-(tert-butoxycarbonylamino)cyclohexanol (A) as a crystallinesolid.

Preparation of trans-4-(tert-butoxycarbonylamino)cyclohexanol (A),method 2. Two 50 L three-neck round bottom flasks were each equippedwith a mechanical stirrer and thermocouple. The flasks were placed in acooling tub, and then each flask was charged with water (8.87 L) andtrans-4-aminocyclohexanol (1479 g). After about 10 to 30 minutes, thetrans-4-aminocyclohexanol had dissolved, and potassium carbonate (1774.6g) was added to each flask. After about 10 to 20 minutes, the potassiumcarbonate had dissolved, and DCM (2.96 L) was charged to each flask. Bocanhydride (3082.6 g) in DCM (1479 mL) was then added to each flask atsuch a rate as to maintain the temperature at 20 to 30° C. An ice/waterbath was used to control the exotherm and to accelerate the addition,which took approximately 1 to 2 hours. A suspension formed during theaddition, and the reaction mixtures were allowed to warm to roomtemperature and stirred overnight, until the reaction was complete basedon the disappearance of the Boc anhydride. Heptane (6 L) was thencharged to each flask, and the mixtures were cooled to approximately 0to 5° C. Solids were collected from each flask by filtration using thesame filter. The combined solids were washed with heptane (6 L) followedby water (8 L). The solids were charged to an appropriately sized crockequipped with a mechanical stirrer. Water (12 L) and heptane (6 L) wereadded, and the resulting suspension was mechanically stirred for 30 to60 minutes. The solids were collected by filtration and then washed on afilter with water (8 L) and heptane (8 L), air-dried on a filter forthree days, and then dried under vacuum at 30 to 35° C. to a constantweight to provide the product as a white solid.

Preparation oftrans-4-(tert-butoxycarbonylamino)cyclohexylmethanesulfonate (B),method 1. A 12 L flask was equipped with a nitrogen flow and amechanical stirrer. Trans-4-(tert-butoxycarbonylamino)cyclohexanol (750g, 3.484 mol) was introduced, followed by tetrahydrofuran (THF, 6.000 L,8 vol), and the mixture was stirred. Triethylamine (370.2 g, 509.9 mL,3.658 mol, 1.05 eq) was added and the mixture was cooled to 0° C.Methanesulfonyl chloride (419.0 g, 283.1 mL, 3.658 mol, 1.05 eq) wascarefully added dropwise, keeping the temperature of the mixture below5° C. After the addition, the mixture was stirred at 0° C. for 3 h, andthen gradually warmed to room temperature (17° C.) and stirred overnight(about 15 h). The mixture was quenched with water (6 vol) and stirredfor 15 min. Ethyl acetate (EtOAc, 9.000 L, 12 vol) was added and thestirring was continued for 15 min. The stirring was stopped and themixture was allowed to stand for 10 min, and the aqueous phase wasremoved. 1 N HCl (6 vol, 4.5 L) was added and stirring was continued for15 min. The stirring stopped and the aqueous phase was removed. 10% w/vNaHCO₃ (4.5 L, 6 vol) was added and the mixture stirred for 10 min.Stirring was stopped and the aqueous phase was removed. Water (6 vol,4.5 L) was added and the mixture was stirred for 10 min. The aqueouslayer was removed, and the organic layer was polish filtered andconcentrated to 4 vol. Heptane (5.5 vol, 4 L) was added and the mixturewas concentrated again to dryness resulting in 988 g oftrans-4-(tert-butoxycarbonylamino)cyclohexylmethanesulfonate.

Preparation oftrans-4-(tert-butoxycarbonylamino)cyclohexylmethanesulfonate (B), method2. A three-neck round bottom flask equipped with a mechanical stirrer,addition funnel, nitrogen inlet, thermocouple and drying tube was placedinto a cooling tub. Trans-4-(tert-butoxycarbonylamino)cyclohexanol (2599g, 12.07 mol, 1.0 eq), tetrahydrofuran (THF) (20.8 L), and triethylamine(1466 g, 14.49 mol, 1.2 eq) were added to the flask. The mixture wascooled with an ice water bath and stirred. Methanesulfonyl chloride(1466 g, 12.80 mol, 1.06 eq) was added dropwise by addition funnel over1 hour. Once the addition was complete, the cooling bath was removed,and the reaction mixture was stirred until TLC indicated the startingmaterial was consumed (about 30 minutes). The reaction mixture was thenquenched with an aqueous solution of hydrochloric acid (223 mL of HCl in6.7 L of water) and EtOAc (10.4 L). The mixture was stirred forapproximately 10 to 20 minutes at ambient temperature and then wastransferred to a separatory funnel. The layers were separated, and theaqueous layer discarded. The organic layer was washed with water (2×4.5L), aqueous saturated sodium bicarbonate solution (1×4.5 L), and driedover anhydrous magnesium sulfate with stirring for 5 to 10 minutes. Themixture was filtered and the filter cake was washed with EtOAc (2×600mL). The combined washes and filtrate were concentrated under reducedpressure at 40° C., leaving a white solid. The solid was taken up inheptane (3 L) and cooled in an ice/methanol cooling tub. More heptane (5L) was added, and the mixture was stirred at 0 to 5° C. for not lessthan 1 hour. The solids were then collected by filtration, washed withcold heptane (0 to 5° C., 2×1.3 L), and dried under vacuum at 40° C. toa constant weight to provide the captioned compound.

Note: A jacketed reactor may be used instead of a round bottom flaskwith a cooling tub and ice bath.

Preparation of trans-4-aminocyclohexylmethanesulfonate (C), method 1.Trans-4-(tert-butoxycarbonylamino)cyclohexylmethanesulfonate (985 g,3.357 mol) was introduced into a 3-neck 12 L flask equipped with astirrer under a nitrogen atmosphere and open vent. DCM (1.970 L, 2 vol)was added at room temperature, and stirring was commenced.Trifluoroacetic acid (TFA) (2.844 kg, 1.922 L, 24.94 mol, 2 vol) wasslowly added to the mixture in two batches of 1 L each. After the firstaddition, the mixture was stirred for 30 min followed by a secondaddition. The mixture was stirred overnight (15 h) at room temperatureresulting in a clear solution. 2-methyltetrahydrofuran (4 vol) was thenadded to the reaction mixture, which was stirred for 1 h. The mixturewas then carefully filtered in a fume hood and suction dried to generate1100 g of TFA salt of trans-4-aminocyclohexylmethanesulfonate withexcess TFA.

Preparation of trans-4-aminocyclohexylmethanesulfonate (C), method 2. A50 L three-neck round bottom flask was equipped with a mechanicalstirrer, addition funnel and thermocouple and was placed into a coolingtub. To the flask was addedtrans-4-(tert-butoxycarbonylamino)cyclohexylmethanesulfonate (3474 g,1.0 eq) and DCM (5.9 L) to the flask. The resulting suspension wasstirred for 5 to 10 minutes at ambient temperature, and thentrifluoroacetic acid (TFA, 5.9 L) was added via addition funnel slowlyover 2.5 hours to control the resulting exotherm and rate of gasevolution. The reaction mixture was stirred at room temperatureovernight and then cooled to 15° C. to 20° C. using an ice water bath.2-Methyl tetrahydrofuran (2-MeTHF, 11.8 L) was then added via theaddition funnel at a rate to maintain the internal temperature below 25°C. (approximately 1.5 hours). The addition of the first 4-5 L of 2-MeTHFwas exothermic. The resulting suspension was stirred for 1 hour. Thesolids were collected by filtration and then washed with 2-MeTHF (2×2.2L) and then dried under vacuum at ambient temperature to a constantweight to provide the captioned compound as a white solid.

Preparation of 7-azabicyclo[2.2.1]heptane hydrochloride (7a), method 1.The TFA salt of trans-4-aminocyclohexylmethanesulfonate (200 g, 650.9mmol) was introduced into a 3-necked flask followed by the addition ofwater (2.200 L, 11 vol). NaOH (78.11 g, 1.953 mol, 3 eq) was slowlyadded, keeping the temperature of the reaction mixture below 25° C. andthe mixture was stirred overnight. DCM (1.4 L, 7 vol) was then added andthe mixture stirred, and the organic layer was separated. The aqueouslayer was then extracted a second time with DCM (1.4 L, 7 vol), and theDCM layers were combined. HCl (108.5 mL, 12M, 1.3020 mol, 2 eq) was thenadded, the mixture was stirred for 30 min and then concentrated on arotary evaporator to dryness. Acetonitrile (10 vol) was added and themixture concentrated. This was repeated 3 times until all trace waterwas azeotropically removed, to provide 7-azabicyclo[2.2.1]heptanehydrochloride. The crude product was recrystallized from acetonitrile(10 vol) to provide 7-azabicyclo[2.2.1]heptane hydrochloride 7a as acolorless crystalline solid. ¹HNMR (DMSO-d⁶) ppm 8.02-8.04 (d);7.23-7.31 (m); 4.59 (s); 3.31 (s); 2.51-3.3 (m); 1.63-1.75 (m);1.45-1.62 (m).

As a note, instead of adding DCM for extraction, the crude product canalso be distilled at about 95° C. to 97° C. and further recrystallized.

Preparation of 7-azabicyclo[2.2.1]heptane hydrochloride (7a), method 2.A 50 L three neck round bottom flask equipped with a mechanical stirrer,addition funnel and thermocouple and was placed into a heating mantle.Trans-4-aminocyclohexylmethanesulfonate trifluoroacetate in (3000 g, 1eq) and water (30 L) were added to the flask. The mixture was stirred,as 50% NaOH (2343 g, 29.29 mol, 3 eq) was added by an addition funnel atsuch a rate as to maintain the temperature below 25° C. because theaddition was mildly exothermic. Upon completion of the NaOH addition,the reaction mixture was stirred overnight at room temperature. Theproduct was recovered by fractional distillation at reflux temperature,(approximately 100° C.) with a head temperature of 95° C. to 98° C. ThepH of each fraction was adjusted to 2 by adding HCl, and concentratedunder reduced pressure at 55° C. to leave a thick paste. Acetonitrile(ACN 1.5 L) was added and the resulting suspension was stirred for 30minutes and then cooled to 0° C. to 5° C. for 1 hour. The solids werecollected by filtration, washed with cold (0 to 5° C.) ACN (2×600 mL),and dried under vacuum at 50° C. to a constant weight.

A 22 L three-neck round bottom flask was equipped with a mechanicalstirrer, thermocouple, and condenser and placed into a heating mantle.The collected solids (2382 g), methanol (4.7 L) and 2-MeTHF (4.7 L) wereadded to the flask. The resulting suspension was stirred and heated toreflux (approximately 65° C.). The reaction flask was transferred to acooling tub, and the mixture was stirred. 2-MeTHF (4.7 L) was then addedvia addition funnel over 30 minutes. The resulting suspension was cooledto 0 to 5° C. and stirred at this temperature for 30 minutes. The solidswere collected by filtration, washed with cold (0 to 5° C.) 2-MeTHF(2×600 mL), and then dried under vacuum at 55° C. to a constant weight.

A 12 L three-neck round bottom flask equipped with a mechanical stirrer,thermocouple, nitrogen inlet and condenser was placed into a heatingmantle. The crude product (2079 g) and ACN (6.2 L) were added to theflask. The resulting suspension was stirred and heated to reflux(approximately 82° C.) for 30 minutes. The flask was transferred to acooling tub and the suspension was slowly cooled to 0 to 5° C. andmaintained at this temperature for 1 hour. The solids were collected byfiltration, washed with cold (0 to 5° C.) ACN (3×600 mL), and driedunder vacuum at 55° C. to a constant weight affording to provide thecaptioned product.

What is claimed is:
 1. A process for preparing Compound 7,

or a pharmaceutically acceptable salt thereof, comprising contactingtrans-4-aminocyclohexanol with Boc anhydride to produce Compound A

contacting Compound A with methanesulfonyl chloride to produce CompoundB

contacting Compound B with trifluoroacetic acid to produce Compound C

contacting Compound C with hydroxide to produce Compound
 7. 2. Theprocess of claim 1, further comprising a process for producing Compound7a,

comprising contacting compound 7 with HCl.
 3. The process of claim 1,wherein trans-4-aminocyclohexanol is contacted with Boc anhydride in thepresence of a solvent and optionally in the presence of a base.
 4. Theprocess of claim 3, wherein the solvent comprises water,dichloromethane, THF, 2-methyltetrahydrofuran, ethanol, methanol,isopropanol, DMF, DMSO, or combinations thereof.
 5. The process of claim4, wherein the solvent is a mixture.
 6. The process of claim 5, whereinthe solvent is a mixture comprising water and dichloromethane.
 7. Theprocess of claim 3, wherein a base is present and the base comprisessodium bicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate, or combinations thereof.
 8. The process of claim 1, whereinCompound A is contacted with methanesulfonyl chloride in the presence ofa solvent and optionally in the presence of a base.
 9. The process ofclaim 8, wherein the solvent comprises tetrahydrofuran.
 10. The processof claim 8, wherein a base is present and the base comprises a tertiaryamine base.
 11. The process of claim 10, wherein the base istriethylamine.
 12. The process of claim 1, wherein Compound B iscontacted with trifluoroacetic acid in the presence of a solvent. 13.The process of claim 12, wherein the solvent is dichloromethane.
 14. Theprocess of claim 1, wherein Compound C is contacted with hydroxide inthe presence of a solvent.
 15. The process of claim 14, wherein thehydroxide is present as sodium hydroxide or potassium hydroxide and thesolvent comprises water.
 16. The process of claim 1, further comprisingdistillation of the reaction mixture and recovery of Compound 7 in apure form.
 17. The process of claim 2, further comprisingrecrystallizing Compound 7 a from acetonitrile.
 18. The process of claim2, further comprising recrystallizing Compound 7 a from a mixture ofmethanol and 2 -methyltetrahydrofuran.
 19. The process of claim 18,wherein the ratio of methanol to 2 -methyltetrahydrofuran is about 1:1.20. A process for preparing Compound 7a,

or a pharmaceutically acceptable salt thereof, comprising contactingtrans-4-aminocyclohexanol with Boc anhydride to produce Compound A

contacting Compound A with methanesulfonyl chloride to produce CompoundB

contacting Compound B with trifluoroacetic acid to produce Compound C

contacting Compound C with hydroxide to produce Compound 7

contacting Compound 7 with HCl to produce Compound 7a.